MECHANISM OF SELECTIVE MOTOR NEURONAL DEATH AFTER EXPOSURE OF SPINAL-CORD TO GLUTAMATE - INVOLVEMENT OF GLUTAMATE-INDUCED NITRIC-OXIDE IN MOTOR-NEURON TOXICITY AND NONMOTOR NEURON PROTECTION

In this study, we analyzed the mechanism of selective motor neuronal d eath, a characteristic of amyotrophic lateral sclerosis, using embryon ic rat spinal cord culture. When dissociated cultures were exposed to low-level glutamate (Glu) coadministered with the Glu transporter inhi bitor L-trans-pyrrolidine-2,4-decarboxylate (PDC) for 24 hours, motor neurons were selectively injured through N-methyl-D-aspartate (NMDA) a nd pha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate r eceptors. Nitric oxide synthase (NOS) inhibitors attenuated this toxic ity, and long-acting nitric oxide (NO) donors damaged motor neurons se lectively. Nonmotor neurons survived after exposure to low-dose Glu/PD C, but Glu-induced toxicity was potentiated by coadministration of an NO-dependent guanylyl cyclase inhibitor. In addition, 8-bromo-cyclic G MP, a soluble cyclic GMP analogue, rescued nonmotor neurons, but not m otor neurons, exposed to high-dose Glu/PDC. Twenty-four hours' incubat ion with PDC elevated the number of neuronal NOS-immunoreactive neuron s by about twofold compared with controls, and a double-staining study , using the motor neuron marker SMI32, revealed that most of them were nonmotor neurons. These findings suggest that selective motor neurona l death caused by chronic low-level exposure to Glu is mediated by the formation of NO in nonmotor neurons, which inversely protects nonmoto r neurons through the guanylyl cyclase-cyclic GMP cascade. Induction o f neuronal NOS in nonmotor neurons might enhance both the toxicity of motor neurons and the protection of nonmotor neurons, which could expl ain the pathology of amyotrophic lateral sclerosis.